乳腺癌组织p27Kip1的表达及其与细胞增殖的关系

目的:研究乳腺癌组织中细胞周期抑制剂p27Kip1的表达及其意义,并探讨其与细胞增殖的关系.方法:应用免疫组化SP法检测80例乳腺癌和20例癌旁正常组织中p27Kip1和增殖细胞核抗原(pro-liferative cell nuclear antigen,PCNA)的表达.结果:乳腺癌组织中p27Kip1高表达率为53.75%(43/80),明显低于癌旁正常组织(P<0.01).p27Kip1表达与组织学分级、TNM分期及淋巴结转移均相关,P<0.05.乳腺癌组织中p27Kip1的表达与PCNA LI呈负相关,r=-0.372,P<0.05.p27Kip1高表达的乳腺癌术后5年无病生存率(DFS)明显高于p27Kip1低表达者(P<0.05).结论:p27Kip1表达缺失可促进肿瘤细胞增殖,是判断乳腺癌发生、发展及预后的有效生物学指标.     

Cyclin-dependent kinase inhibitor p27(Kip1) expression in transitional cell carcinoma of renal pelvis and ureter

We examined the expression and significance of p27^Kip1 protein in 79 patients with transitional cell carcinoma of the renal pelvis and ureter. Immunohistochemical staining of archival tissue specimens was done using a labeled streptavidin–biotin–peroxidase method. There was no significant association between p27^Kip1 labeling index and histologic grade or pathologic stage. Patients with p27^Kip1 labeling indices of 27 or greater had more favorable prognoses in comparison to those with p27^kip1 labeling indices less than 27 (P<0.01). Multivariate analysis indicated that p27^Kip1 had an independent predictive prognostic value (P<0.05). The p27^Kip1 may be a novel prognostic marker for transitional cell carcinoma of the renal pelvis and ureter.     

宫颈癌中p27Kip1基因的表达与体外药物敏感性的关系

背景与目的：p27^Kip1基因是调控细胞周期并抑制细胞分裂的重要基因。它与诱导肿瘤细胞的凋亡和化疗药物的耐药也有关系。本文旨在探讨宫颈癌组织中p27^Kip1基因的表达与体外药敏的关系。方法：采用MTT法检测了部分化疗药物在46例宫颈癌组织中的抑制率，并采用免疫组织化学方法检测了癌组织中p27^Kip1基因的表达。结果：宫颈癌组织中p27^Kip1表达的阳性率为15.2％（7／46）。顺铂（DDP）、表柔比星（E—ADM）、替尼泊苷（VM26）、紫杉醇（Taxol）、吉西他滨（Gemzar）、氟尿嘧啶（5-FU）和BLM的平均抑制率分别为47.6％、38．0％、42．7％、27．4％、23.0％、26.3％和24．8％。DDP、VM26和Taxol在p27^Kip1表达阴性的宫颈癌标本中的抑制率显著低于阳性标本（P〈0.05），而在其他药物中差异无显著性。结论：p27^Kip1的表达可作为判断肿瘤对化疗药物的敏感性的指标，指导临床用药。     

Low p27Kip1 expression is associated with poor prognosis in oral squamous cell carcinoma

BACKGROUND: p27Kip1 is a cyclin-dependent kinase inhibitor which regulates the progression of cells from the G1-into the S-phase in a cell cycle. Loss of p27Kip1 is associated with disease progression and an unfavorable outcome in several malignancies. The purpose of this study was to determine whether p27Kip1 expression can be a useful prognostic factor in oral squamous cell carcinoma (SCC) patients. PATIENTS AND METHODS: p27Kip1 expression was investigated by immunohistochemistry in tissue samples from 81 patients with oral SCC. The associations between p27Kip1 expression and clinicopathological characteristics and patient survival were also analyzed. RESULTS: Significant associations were found between p27Kip1 expression and histological grade (p = 0.010), therapeutic effect (p = 0.004) and patient outcome (p = 0.005). The 5-year survival rates of p27Kip1 high- and low-expression tumours were 80.4% and 56.7%, respectively, this difference being significant (p = 0.009) by log-rank test. Multivariate analysis revealed that reduced term survival was related to low levels of p27Kip1 expression (p = 0.008) and advanced stage (stages III and IV) (p = 0.003). CONCLUSION: These results suggest that reduction of p27Kip1 plays an important role in the progression of oral SCC and is considered to be a useful prognostic factor in oral SCC patients.     

Prognostic implication of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma: a tissue microarray study

Background

p27^Kip1 plays a major role as a negative regulator of the cell cycle. The regulation of p27^Kip1 degradation is mediated by its specific ubiquitin ligase subunits S-phase kinase protein (Skp) 2 and cyclin-dependent kinase subunit (Cks) 1. However, little is known regarding the prognostic utility of p27^Kip1, Skp2 and Cks1 expression in renal cell carcinoma.

Methods

Immunohistochemistry was performed for p27^Kip1, Skp2 and Cks1 in tissue microarrays of 482 renal cell carcinomas with follow-up. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance.

Results

Immunoreactivity of p27^Kip1, Skp2 and Cks1 was noted in 357, 71 and 82 patients, respectively. Skp2 and Cks1 expression were not noted in chromophobe cancers. A strong correlation was found between Skp2 and Cks1 expression (P < 0.001), both of which were inversely related to p27^Kip1 levels (P = 0.006 and P < 0.001), especially in primary and clear-cell cancers. Low p27^Kip1 expression and Skp2 expression were correlated with larger tumor size and higher stage, as well as tumor necrosis. Cks1 expression was only correlated with tumor size. In univariate analysis, low p27^Kip1 expression, Skp2 and Cks1 expression were all associated with a poor prognosis, while in multivariate analysis, only low p27^Kip1 expression were independent prognostic factors for both cancer specific survival and recurrence-free survival in patients with RCC.

Conclusion

Our results suggest that immunohistochemical expression levels of p27^Kip1, Skp2 and Cks1 may serve as markers with prognostic value in renal cell carcinoma.     

Prognostic role of p27(Kip1) expression in oral squamous cell carcinoma in Taiwan

The cyclin-dependent kinase inhibitor p27(Kip1) can inhibit the G1 to S transition of the cell cycle and is a putative tumor suppressor. Decreased expression of p27(Kip1) protein has been correlated with poor prognosis in a variety of human tumors. We examined the expression of p27(Kip1) in oral squamous cell carcinoma (SCC), epithelial dysplasia (ED) and normal oral mucosa (NOM) using antibodies to p27(Kip1). Positive p27(Kip1) nuclear staining was detected in all the specimems from ED and NOM, whereas positive p27(Kip1) staining was observed in 16 of the 63 (25%) cases of oral SCC. The labeling index for p27(Kip1) protein was significantly reduced from NOM through ED to oral SCCs, indicating that changes of p27(Kip1) protein expression may be an early event in oral carcinogenesis in Taiwan. The Kaplan-Meier analysis showed patients with p27(Kip1)-positive tumors had significantly higher overall survival than those with p27(Kip1)-negative tumors in a total of 63 patients (P=0.015) and 47 patients with areca quid chewing habit (P=0.026). Multivariate analysis showed decreased p27(Kip1) protein expression was an independent significant predictor of poor overall survival in the patients with oral SCCs. These results indicate that p27(Kip1) protein expression may serve as a putative new adjuvant prognostic marker for routine assessment of oral SCC patients.     

p27Kip1与消化系肿瘤关系的研究进展

p27Kipl定位于染色体12p13,含2个外显p27-方面抑制CDK激活,另一方面尚可抑制激活后的cyclin-CDK的活性,p27不仅在细胞周期增殖调控中起关键作用。而且与细胞的分化发育及凋亡也有关系。p27蛋白缺失或低表达在消化系恶性肿瘤中是一个较为普遍的现象。且低表达预示不良结局。     

Low expression of p27(Kip1) is associated with tumor size and poor prognosis in patients with renal cell carcinoma

BACKGROUND: Proliferative activity in tumors depends on regulation of the cell cycle. p27(Kip1) (p27) plays a pivotal role as a negative regulator of the cell cycle. A decrease in p27 expression has been reported in many kinds of tumors, but little is known regarding p27 in patients with renal cell carcinoma (RCC). METHODS: Expression of p27 and the related cyclins (cyclin A, cyclin E, and cyclin D1) was examined immunohistochemically in 67 patients with of clear cell RCC. The Ki-67 labeling index (MIB-1 LI) and clinicopathologic parameters related to a poor prognosis also were analyzed. To determine their prognostic significance, univariate and multivariate survival analyses were performed. RESULTS: In tumors, there was considerable immunoreactivity for cyclin A, cyclin D1, and MIB-1, and the mean values for each were 1.08%, 16.1%, and 1.5%, respectively. Cyclin E expression was rare. The expression of p27 was correlated strongly with the expression of cyclin A (correlation coefficient, 0.432; P < 0.0004) and cyclin D1 (correlation coefficient, 0.476; P < 0.0004). Also, an inverse correlation was present between p27 expression and tumor size (P = 0.0377). In univariate analysis, the unfavorable prognostic factors were high TNM stage (P < 0.0001), large tumor size (P = 0.0016), high histologic grade (P = 0.0104), and low p27 expression (P < 0.0001). In multivariate analysis, high TNM stage (P = 0.0035) and low p27 expression (P = 0.0235) were independent prognostic factors for disease specific survival in patients with RCC. CONCLUSIONS: The results of this study suggest that low p27 expression may be a significant and independent, unfavorable prognostic factor in patients with renal cell carcinoma.     

p27Kip1、PLK1在食管鳞癌中表达的临床意义

目的:探讨p27Kip1(p27)、polo-like kinase1(PLK1)在食管鳞癌(ESCC)与其癌旁组织中的差异表达及其相关性,分析其基因表达差异与ESCC的临床病理特点及蛋白表达与预后的关系。方法:RT-PCR和免疫组化检测70对ESCC与其癌旁组织中p27、PLK1的mRNA和蛋白表达情况。结果:比较70对ESCC与其癌旁组织中p27及PLK1的相对表达,p27在46例(66%)癌组织中相对表达下降,24例(34%)癌组织中相对表达增高,比较有统计学差异(P＜0.01);而PLK1在63例(90%)癌组织中相对表达增高,7例(10%)癌组织中相对表达下降,比较有统计学差异(P＜0.01);且癌组织中PLK1及p27相对低表达与患者的病理进展、淋巴结的转移和临床分期相一致(P＜0.05);癌组织中PLK1伴p27胞浆表达阳性的患者与癌组织中PLK1伴p27胞核表达阳性的患者比较,术后生存期明显缩短(P＜0.01)。结论:p27与PLK1在ESCC组织中的差异性表达与患者的临床病理特点密切相关,癌组织中PLK1伴胞浆p27表达阳性的患者预后更差。     

Positive correlation between P27Kip1 expression and progression of human esophageal squamous cell carcinoma

p27^Kip1, one of the cyclin-dependent kinase (CDK) inhibitors (CDKIs), blocks progression from G₁ to S phase by binding cyclin D1-CDK4 and/or cyclin E-CDK2 and inhibiting their activities. Reflecting the function of p27 as a CDKIin vitro, a reduced expression of protein p27 has recently been reported to be associated with tumor aggressiveness in some types of human cancers. In the present study, we examined the relationships between immunohistochemically detected expression of p27, cyclin D1, cyclin E proteins and clinico-pathological findings in 77 patients with esophageal squamous cell carcinoma (SCC). Using specific monoclonal antibodies to p27, cyclin D1 and cyclin E proteins, positive immunostaining in the nuclei was observed in 32.5% (25/77), 27.3% (21/77) and 29.6% (21/71) of patients, respectively. There were no statistically significant relationships among the expressions of these 3 proteins. Using the Kaplan-Meier's method, p27 and cyclin D1 expressions were found to be independently associated with poor prognosis. When all parameters were combined into a multivariate regression analysis using the Cox model, the expressions of p27 and cyclin D1 retained a predictive value for survival. In contrast to former reports supporting a tumor-suppressive function of p27, our results suggest that altered expression of p27 and cyclin D1 may be associated with the progression of human esophageal SCC, in which cyclin E may well not play any central role. Int. J. Cancer (Pred. Oncol.) 79:439–443, 1998. © 1998 Wiley-Liss, Inc.     

上皮性肿瘤细胞中Snail与E-cadherin的表达及其与体外侵袭性的关系

目的 研究上皮性肿瘤细胞Snail与E-cadherin的表达以及与瘤细胞表型、转移潜能的关系。方法 采用Northern blot、共聚焦激光显微镜研究6株不同组织来源、不同分化程度及转移潜能的上皮性肿瘤细胞、1株正常上皮细胞、1株成纤维细胞中Snail与E-cadherin mRNA和蛋白表达与定位;Boyden小室体外侵袭实验反映细胞的转移潜能。结果 在分化程度较高的癌细胞和对照正常上皮细胞中,E-cadherin mRNA与蛋白表达较强,而Snail表达缺如;在分化程度低、转移潜能高的癌细胞和对照成纤维细胞中,E-cadherin、Snail mRNA及蛋白表达与上述情况相反。E-cadherin多定位于细胞胞浆和胞膜,Snail主要定位于胞核和胞浆。结论 在上皮性肿瘤细胞中E-cadherin和Snail在mRNA与蛋白表达水平上存在逆反关系,且与细胞分化、转移潜能相关。     

Prognostic implications of expression of the cell cycle inhibitor protein p27Kip1

Mitogenic and growth inhibitory signals influence the activity of a family of cyclin dependent kinases (cdks). p27 is an important cdk inhibitor, acting in G1 to inhibit cyclin-cdks. As negative growth regulators, the cdk inhibitors may function as tumor suppressors. While the p16 gene plays a tumor suppressor role in cancers, p27 gene mutations have been identified only rarely. While high levels of p27 protein are expressed in normal human mammary epithelium, loss of p27 is frequent and is of independent prognostic significance in breast cancers. Low p27 is also a poor prognostic factor in colon, gastric, esophageal, lung, and prostate carcinomas, and enhanced proteasomal degradation may underlie loss of p27 in tumor cells. Loss of p27 has not been significantly correlated with tumor proliferation in a number of studies and may reflect alterations in differentiation and adhesion-dependent growth regulation germane to oncogenesis and tumor progression. Efforts to confirm the prognostic value of p27 are under way in a number of large breast cancer studies. These studies may also indicate whether loss of p27 in association with other traditional or novel markers has greater prognostic potential than each factor alone. p27 immunostaining is inexpensive and reliable and may become part of the routine histopathologic processing of tumors in the near future. Widespread application of p27 in prognostic testing will require greater uniformity in scoring techniques and determination of the cut off levels which distinguish individuals at high and low risk of cancer recurrence and death. Finally, the greatest utility of p27 may lie in the information it sheds on the biology of aberrant growth regulation in breast cancer and the potential to use this in the generation of novel therapeutic strategies.     

乳腺癌组织p27^kip1的表达及其与细胞增殖的关系

目的：研究乳腺癌组织中细胞周期抑制剂 p27^kip1的表达及其意义,并探讨其与细胞增殖的关系。方法：应用免疫组化SP法检测80例乳腺癌和20例癌旁正常组织中 p27^kip1和增殖细胞核抗原（proliferative cell nuclear antigen,PCNA）的表达。结果：乳腺癌组织中 p27^kip1高表达率为53．75％（43／80）,明显低于癌旁正常组织（P〈0．01）。 p27^kip1表达与组织学分级、TNM分期及淋巴结转移均相关,P〈0．05。乳腺癌组织中 p27^kip1的表达与PCNALI呈负相关,r=0．372,P〈0．05。 p27^kip1高表达的乳腺癌术后5年无病生存率（DFS）明显高于 p27^kip1低表达者（P〈0．05）。结论： p27^kip1表达缺失可促进肿瘤细胞增殖,是判断乳腺癌发生、发展及预后的有效生物学指标。     

食管鳞状细胞癌组织中细胞凋亡与P27Kip1、PCNA同步表达的关系

目的 :探讨食管鳞状细胞癌组织中细胞凋亡、细胞增殖相关基因PCNA及P2 7Kip1相互之间的关系 ,以及与食管鳞癌发生、发展及预后的关系。方法 :4 7例原发性食管鳞状细胞癌手术切除标本为一组 ,2 0例正常食管粘膜组织为对照组。采用免疫组织化学方法 (S ABC法 )对两组的PCNA、P2 7Kip1的表达水平进行检测 ,采用TdT介导的脱氧尿苷酸缺口末端标记法 (TUNEL法 )对两组的细胞凋亡进行检测。结果 :4 7例食管鳞癌组织中 ,P2 7Kip1阳性表达率、平均增殖指数 (PI)、平均凋亡指数 (AI)、PI/AI均较正常食管粘膜组有明显差异 (P <0 .0 5 )。P2 7Kip1蛋白的表达及PI与食管鳞癌的病理分级、淋巴结转移、肿瘤的浸润深度以及临床分期有关 (P <0 .0 5 ) ,而与肿瘤的部位和病变范围无关。AI则与肿瘤病理分级有关 (P <0 .0 5 )。PI/AI比值与肿瘤病理分级、淋巴结转移有关 (P <0 .0 5 )。P2 7Kip1蛋白表达阳性组食管鳞癌术后五年生存率显著高于表达阴性组 ;PCNA低表达组食管鳞癌术后五年生存率显著高于高表达组 (P <0 .0 5 )。结论 :PCNA的异常表达状态能够较好的反映食管鳞癌的浸润、转移能力 ,有一定的预后判定价值。增殖与凋亡的失衡贯穿于食管鳞癌的发生、发展过程。P2 7Kip1在食管鳞癌中表达的缺失与肿瘤的病理分级、浸润     

Inactivation of PTEN is associated with a low p27Kip1 protein expression in breast carcinoma

BACKGROUND: It was previously demonstrated that PTEN protein expression is reduced in 67 of 236 (28%) breast carcinomas. Recent experimental studies suggested that the cell cycle inhibitor p27Kip1 (p27) is a downstream mediator through which PTEN negatively regulates cell cycle progression. METHODS: The immunohistochemic expression of p27 and PTEN protein expression was evaluated in a series of 228 invasive ductal carcinomas of the breast. RESULTS: PTEN protein expression was found to have decreased in 65 of 228 (29%) cases, while the nuclear accumulation of p27 protein was low in 99 of 228 (43%) cases. A reduced PTEN protein expression correlated significantly (P = 0.0214) with a low p27 protein expression. Univariate analysis indicated that the patients demonstrating a combined decrease in PTEN and p27 protein expression have a significantly (P = 0.0044) worse disease-free survival (DFS) than those with other combinations of these two protein expression patterns, while multivariate analysis indicated that the lymph node status, MIB-1 counts, and the combination of PTEN/p27 protein expression (P = 0.0452) are independently significant prognostic factors for DFS. CONCLUSIONS: A reduced PTEN protein expression correlated significantly with a low p27 protein expression in breast carcinoma. The finding that the patients with a combined decrease in both protein expressions had a poor prognosis thus suggests that a combined loss of PTEN and p27 function is associated with an aggressive phenotype in breast carcinoma.     

Reduced expression of p27(Kip1) correlates with an early stage of cancer invasion in oral squamous cell carcinoma

Down-regulation of p27(Kip1) has been reported to correlate with poor survival of various carcinoma patients including oral squamous cell carcinomas (OSCCs). It is still unclear, however, at what stage of oral carcinogenesis the down-regulation of this protein occurs. In this study, therefore, we evaluated immunoexpression of p27(Kip1) protein in 17 cases of oral epithelial dysplasia and succeeding invasive OSCC in the same patient. We reported here that 88% cases showed high p27(Kip1) expression in dysplastic lesions, whereas 82% cases of succeeding invasive OSCC exhibited reduced expression. The reduction of p27(Kip1) expression was also observed in 16 of 19 (84%) early invasive lesions and well correlated with Ki-67 expression which is good indicator of cell proliferation. We also investigated immunoexpression of p53 protein of which abnormality has been known to occur during the early stage of OSCC development. Overexpression of p53 protein was demonstrated in 29% of dysplastic lesions, 42% of early invasive and 71% of invasive OSCCs. These findings suggest that abnormalities of both p53 and p27(Kip1) are involved in the carcinogenesis of OSCC, but they seem to play their role at different stages of oral cancer development, respectively. Reduced expression of p27(Kip1) may concern the cancer invasion directly or indirectly as well as abnormal proliferation.     

PTEN and p27Kip1 are not downregulated in the majority of renal cell carcinomas--implications for Akt activation

Activation of the PKB/Akt pathway is supposed to substantially contribute to the pathogenesis and progression of malignant disease. The present study aimed at determining the occurrence of an impaired PTEN and p27Kip1 expression alone or in combination in a renal cell carcinoma to further clarify the role of Akt-pathway-associated proteins for the development and/or progression of this malignant disease. By using tissue microarray analysis, tissue samples from renal cell cancers and the corresponding benign tissue samples were investigated for expression of the PTEN, pAkt and p27Kip1 protein by immunohistochemistry. Additionally, a Western blot and RT-PCR analysis was performed to verify the results obtained from the immunohistochemical approach and to further clarify the mechanisms underlying the regulation of both proteins in renal cell cancer. Western blot analysis revealed an overexpression of PTEN and p27Kip1 in renal cell cancer samples and a significantly elevated expression of both proteins when compared with the corresponding benign tissue (p<0.0001 and p<0.0005). The latter finding was confirmed by real-time RT-PCR (p<0.05 and p<0.01) and immunohistochemistry (p<0.001 and p<0.0001). PTEN and p27Kip1 expression were positively correlated with each other both in the tumour and benign tissue (p<0.001 and p<0.0001). We concluded that a strong expression of PTEN in renal cell cancer did not block the PI3K-mediated phosphorylation of Akt in the tumour specimens analysed. Furthermore, Akt activation may not result in a decreased p27Kip1, the latter being retained and overexpressed in the majority of renal cell cancers when compared with the corresponding benign renal parenchyma.